Research Papers:

Dendritic cell-derived nitric oxide inhibits the differentiation of effector dendritic cells

Chuanping Si, Ruihua Zhang _, Tianshu Wu, Geming Lu, Yuan Hu, Hui Zhang, Feihong Xu, Peter Wei, Kang Chen, Hua Tang, Garabet Yeretssian and Huabao Xiong

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Oncotarget. 2016; 7:74834-74845. https://doi.org/10.18632/oncotarget.11361

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Chuanping Si1,*, Ruihua Zhang2,*, Tianshu Wu2, Geming Lu2, Yuan Hu2, Hui Zhang1, Feihong Xu2, Peter Wei2, Kang Chen3, Hua Tang4, Garabet Yeretssian2, Huabao Xiong1,2

1Institute of Immunology and Molecular Medicine, Jining Medical College, Shandong 272067, China

2Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

3Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48201, USA

4Institute of Immunology, Taishan Medical University, Tai’an, Shandong 271000, China

*These authors have contributed equally to this work

Correspondence to:

Ruihua Zhang, email: [email protected]

Huabao Xiong, email: [email protected]

Keywords: dendritic cell, iNOS

Received: April 14, 2016     Accepted: July 27, 2016     Published: August 18, 2016


Dendritic cells (DCs) play a pivotal role in the development of effective immune defense while avoiding detrimental inflammation and autoimmunity by regulating the balance of adaptive immunity and immune tolerance. However, the mechanisms that govern the effector and regulatory functions of DCs are incompletely understood. Here, we show that DC-derived nitric oxide (NO) controls the balance of effector and regulatory DC differentiation. Mice deficient in the NO-producing enzyme inducible nitric oxide synthase (iNOS) harbored increased effector DCs that produced interleukin-12, tumor necrosis factor (TNF) and IL-6 but normal numbers of regulatory DCs that expressed IL-10 and programmed cell death-1 (PD-1). Furthermore, an iNOS-specific inhibitor selectively enhanced effector DC differentiation, mimicking the effect of iNOS deficiency in mice. Conversely, an NO donor significantly suppressed effector DC development. Furthermore, iNOS–/– DCs supported enhanced T cell activation and proliferation. Finally iNOS−/− mice infected with the enteric pathogen Citrobacter rodentium suffered more severe intestinal inflammation with concomitant expansion of effector DCs in colon and spleen. Collectively, our results demonstrate that DC-derived iNOS restrains effector DC development, and offer the basis of therapeutic targeting of iNOS in DCs to treat autoimmune and inflammatory diseases.

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